Linage priming and cell type proportioning depends on the interplay between stochastic and deterministic factors

Embryonic stem cells (ESCs) can break symmetry and differentiate along different lineages, even when exposed to a seemingly identical environment. It is thought that this priming of cells towards different lineages is due to cell-cell variation, although the underlying mechanisms are poorly understood. To address this, we exploit the tractability of the social amoeba Dictyostelium discoideum , where cell fate choice also does not depend on spatial cues. We develop and test a model to explain quantitative experimental single cell observations of probabilistic differentiation. The model suggests that cell cycle position affects lineage choice, as previously shown, but that stochastic cell-cell variation also plays a key role. Single cell sequencing reveals genes strongly associated with fate choice exhibit extensive stochastic cell-cell expression variation. Like lineage priming genes in ESCs, they are associated with specific epigenetic modifications, which when perturbed affect their expression and disrupt fate choice. We suggest this represents an adaptive mechanism that increases developmental robustness against perturbations that affect deterministic signals.